Hypercholesterolemia is known to be one of the prime risk factors for atherosclerosis and coronary heart disease, the leading cause of death and disability in western countries. The bile acid sequestrants seem to be moderately effective as antihyperchloesterolemic agents but they must be consumed in large quantities, i.e., several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of semi-synthetic and totally synthetic analogs thereof. For example, simvastatin, wherein the 8-acyl moiety is 2,2-dimethylbutyryl, is an even more potent HMG-CoA reductase inhibitor than lovastatin.
Simvastatin is now commercially available as ZOCOR.RTM. in some markets.
The preparation of simvastatin was originally described in U.S. Pat. No. 4,444,784. The process involves deacylation of lovastatin followed by a subsequent acylation with the 2,2-dimethylbutyryl moiety. Simvastatin has also been prepared by the alpha alkylation of the lovastatin ester moiety as described in U.S. Pat. Nos. 4,582,915 and 4,820,850.
The recent commercial introduction of simvastatin has provided a need for a high yielding process for the production of simvastatin, which is economically efficient and environmentally sound.